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Preparation method of three-membered ring compound

A compound and three-membered ring technology, which is applied in the field of preparation of camptothecin intermediate three-membered ring compounds, can solve the problems of unfavorable mass production, harsh reaction conditions, and high cost of raw materials, and achieve cheap catalysts, short synthetic routes, and cheap raw materials Effect

Active Publication Date: 2021-02-02
上海禧耀医药科技有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0009] In this method, the cost of raw materials is high, and the yield of some steps is low, and the reaction conditions are harsh, which is not conducive to mass production

Method used

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  • Preparation method of three-membered ring compound
  • Preparation method of three-membered ring compound
  • Preparation method of three-membered ring compound

Examples

Experimental program
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Effect test

Embodiment 1

[0027] Add 13.5 mL of 2,2,6,6-tetramethylpiperidine into the reaction flask, add 150 mL of tetrahydrofuran under nitrogen atmosphere, stir, and cool down to -78°C. Slowly add 45 mL of 2.5M n-butyllithium solution in tetrahydrofuran to the bottle dropwise, and react for 1 hour after the dropwise addition. 5 g of 6-chloro-2-methoxynicotinic acid was dissolved in 25 mL of tetrahydrofuran, and slowly dropped into the reaction flask, and the reaction was completed for 1 hour. Add 7.9 mL of 1-penten-3-one into 25 mL of tetrahydrofuran, slowly drop it into the reaction bottle, and finish the reaction for 1 hour. After the reaction was complete, the system was placed at room temperature for 5 minutes, then 20 mL of concentrated hydrochloric acid was added and stirred for 1 hour, then 50 mL of water was added to dissolve the solid, extracted with ethyl acetate (100 mL×3), the organic layer was collected, and washed with saturated brine (100 mL×2). Dry over anhydrous sodium sulfate, sp...

Embodiment 2

[0029] Add 4.6 g of 6-chloro-1-ethyl-4-methoxy-1-vinyl[3,4-c]pyridin-3(1H)-one into the reaction flask, add 25 mL of ethanol and stir at room temperature for 30 minutes. The temperature of the reaction system was lowered to 0° C., 2.8 g of sodium borohydride was added in batches, and the reaction was stirred at room temperature for 24 hours. After the reaction was complete, 2 mL of hydrochloric acid was added, extracted with dichloromethane (25 mL×3), the organic layer was collected, washed with saturated brine (25 mL×2), and dried over anhydrous sodium sulfate. Dichloromethane was decompressed to obtain 4.5g transparent oily liquid compound 3-(6-chloro-3-(hydroxymethyl)-2-methoxypyridin-4-yl)pent-1-en-3-ol, Yield 98%. 1 H NMR (400MHz, CDCl 3 )δ6.94(s,1H),6.07(dd,J=17.3,10.7Hz,1H),5.23(dd,J=14.0,6.0Hz,2H),4.84–4.68(m,2H),3.96(s , 3H), 2.02 (dq, J = 14.6, 7.4Hz, 1H), 1.90 (dq, J = 14.6, 7.4Hz, 1H), 0.89 (t, J = 7.4Hz, 3H).

Embodiment 3

[0031] Dissolve 4.5 g of 3-(6-chloro-3-(hydroxymethyl)-2-methoxypyridin-4-yl)pent-1-en-3-ol in 500 mL of dichloromethane and cool to -70 ℃, ozone was passed into the solvent for 1 hour, and after the reaction was completed, 1 mL of dimethyl sulfide was added to rise to room temperature and stirred for 30 minutes, and the solvent was rotated to obtain a white solid 6-chloro-4-ethyl-8-methoxy- 4.4 g of 3,4-dihydro-1H-pyrano[3,4-c]pyridine-3,4-diol, yield 97.8%. 1 H NMR (400MHz, DMSO) δ7.07(s, 1H), 6.81(d, J=4.5Hz, 1H), 4.99(s, 1H), 4.96(d, J=4.5Hz, 1H), 4.51(dd , J=38.9, 16.2Hz, 2H), 3.87(s, 3H), 1.70–1.52(m, 2H), 0.81(t, J=7.3Hz, 3H).

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Abstract

The invention discloses a preparation method of a three-membered ring compound. The compound is an important intermediate for preparing racemic camptothecin compounds. The method comprises the following steps of: taking 6-chlorine-2-methoxy nicotinic acid as an initial raw material, and reacting the 6-chlorine-2-methoxy nicotinic acid with 1-pentene-3-ketone and a lithium reagent to obtain a lactone compound; reducing lactone to obtain a diol compound; oxidizing the diol compound to obtain a hemiacetal compound; oxidizing the hemiacetal compound to obtain a lactone compound; inserting carbonylinto the lactone compound to obtain a 6-position n-propyl ester compound; demethylating the n-propyl ester compound to form a pyridone compound; and finally, reacting the pyridone compound with tert-butyl acrylate, and decarboxylating to obtain the three-membered ring compound, namely 4-ethyl-4-hydroxyl-7, 8-dihydro-1H-pyrano [3, 4-f] indolizine-3, 6, 10 (4H)-triketone. The method is high in yield, short in synthesis route, simple and cheap in raw materials and easy in purification.

Description

technical field [0001] The invention belongs to the technical field of organic chemistry, and in particular relates to a preparation method of a racemic camptothecin intermediate three-membered ring compound. Background technique [0002] Camptothecin (CPT) is an alkaloid obtained from Camptothecin bark in central China by Wall and Wani in 1958. Camptothecin is a five-membered quinoline alkaloid, which has become one of the focuses of antitumor drug research because of its remarkable antitumor activity in vivo and in vitro animal experiments. At present, three camptothecin compounds have been approved for the clinical treatment of malignant tumors, among which irinotecan was approved for colorectal cancer in 1994, topotecan was approved for ovarian cancer in 1996, and belotecan was approved for use in 1996. It was approved for prostate cancer in 2005. [0003] The synthesis and transformation of camptothecin is another important field of camptothecin research. For the tra...

Claims

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Application Information

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IPC IPC(8): C07D491/147
CPCC07D491/147
Inventor 吕伟邵平譞王磊
Owner 上海禧耀医药科技有限公司
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